Transgenic Mice Expressing a Real-Time Reporter for Cellular cAMP in a Tissue-Selective and Inducible Manner
Nirupa Chaudhari and Stephen D. Roper
Problem
Cyclic AMP (cAMP) mediates the response to hormones, neurotransmitters and other molecules in practically every tissue of the body. Until now, it has been difficult to monitor the dynamics and spatial location of cAMP accurately. Visually monitoring cAMP would allow investigators to record this molecule in intact live tissues and individual cells.
Solution
The inventors have generated a unique transgenic mouse that is able to express an inducible fluorescent cAMP reporter in targeted cells and tissues. To achieve this, transgenic mice carrying the newly generated and unique cAMP reporter are mated with mice carrying an appropriate, tissue-specific, antibiotic-sensitive triggering mechanism in their genome. Mice tailored to a specific tissue can be readily generated. By injecting a commonly available antibiotic, researchers can then induce the synthesis of the cAMP reporter in pre-specified cells. Using this mouse model, cAMP can be examined in intact organs, tissues and cells both in vitro and in vivo. The transgenic mouse will make it possible to monitor how intracellular cAMP levels change in response to metabolites, transmitters, hormones, and drugs in real time and with high spatial resolution (i.e., single cells and even subcellular regions).
Competitive Advantage
This is the only mouse model available that allows responses to drugs, metabolites, transmitters, hormones, pharmaceuticals, etc. to be monitored visually in vivo. Furthermore, the response can be seen in real time with high spatial resolution.
Applications
This mouse will allow the determination of:
(1)Side effects of many drugs in target tissues;
(2)Responses to circulating hormones in intact tissues and organs;
(3)Responses of cells and tissues to metabolites and nutrients, such as circulating glucose;
(4) Neuronal activity in the central, autonomic, and peripheral nervous systems that results in changes in cAMP;
(5)Responses of cardiac cells to multiple therapies;
(6) Response of the digestive system to food industry additives;
(7)Basic, translational and clinical scientists could use the mouse to examine cAMP-mediated signaling in any tissue;
(8)Pharmaceutical and academic researchers could potentially use this mouse to monitor responses to existing drugs and develop new ones;
(9)This mouse could be used to test the effects of treatments affecting the brain, spinal cord, or autonomic nervous system;
(10) Because of the widespread occurrence of cAMP as a second messenger in nearly every tissue in the body, the new transgenic mice could be used to study an endless list of cellular mechanisms in health and disease.
Patent Status
International Patent Application WO/2008/067032 entitled "TRANSGENIC MICE EXPRESSING A REAL-TIME REPORTER FOR CELLULAR CAMP IN A TISSUE-SELECTIVE AND INDUCIBLE MANNER" was published on June 5, 2008.
Licensing Opportunity
We are seeking collaborative research and commercial options including an exclusive license for this mouse.
About the Inventors
Nirupa Chaudhari, Ph.D. is an Associate Professor of Physiology and Biophysics at the School of Medicine. Dr. Chaudhari's work focuses on understanding how the body's taste buds work and received a one-year extension of her appointment to the Study Section for Integrative, Functional, and Cognitive Neuroscience of the Center for Scientific Review, National Institutes of Health. Dr. Chaudhari works closely with fellow Miller School professor Dr. Roper, and has been instrumental in identifying receptors for umami-savory flavors in meats, cheeses, some vegetables, and monosodium glutamate.
Stephen D. Roper, Ph.D., is a Professor in the Department of Physiology and Biophysics, whose work focuses on understanding how the body's taste buds work. He was instrumental in cloning and identifying the molecular receptors for "umami" taste. The identification, says Roper, firmly established the validity of umami as a fifth taste, after sweet, sour, salty, and bitter. Dr. Roper is currently working on better ways to buffer the bitterness of good-for-you edibles. He is one of four prominent national researchers appointed to the Scientific Advisory Board of Linguagen Corp., a biotechnology firm that identifies and develops compounds to improve the taste of pharmaceutical, food, and beverage products.
Selected References
Kim JW, C Roberts, Y Maruyama, S Berg, S Roper and N Chaudhari (2006) Faithful expression of GFP from the PLC 2 promoter in a functional class of taste receptor cells. Chem Senses 31:213-219.
Maruyama Y, E Pereira, RF Margolskee, N Chaudhari and SD Roper (2006) Umami responses in mouse taste cells indicate more than one receptor. J Neurosci., 26: 2227-2234.
Trubey KR, SS Culpepper, Y Maruyama, SC Kinnamon and N Chaudhari (2006) Tastants evoke a cAMP signal that is independent of calcium signaling. Am J Physiol Cell Physiol 291: C237-C244.
DeFazio RA, G Dvoryanchikov, JW Kim, Y Maruyama, SD Roper and N Chaudhari (2006) Separate populations of receptor cells and pre-synaptic cells in mouse taste buds. J Neurosci. 26: 3971-3980.
